Throughout this application, various publications are referenced. The full citation of these publications is provided in a bibliography immediately before the claims. The disclosures of these publications are hereby incorporated by reference to more fully describe the state of the art at the time the invention was made.
The following invention was made through support from grant number GM 33369 from the National Institutes of Health, grant number DCB 8710283 from the National Science Foundation and grant number CRIS 6612-42000-004 to the United States Department of Agriculture. The United States government has rights in the invention.
Fusarium moniliforme (Sheldon) is one of the most prevalent fungi on maize, other grains, and agricultural commodities in the United States and throughout the world (1). Culture materials from certain isolates of (and grains naturally contaminated with) F. moniliforme have been shown to be toxic and carcinogenic for animals (2-5); furthermore, consumption of contaminated maize has been correlated with esophageal cancer in areas of southern Africa, China, and other countries (6-8). Several mycotoxins, termed fumonisins, have been isolated from extracts of F. moniliforme (9) and naturally contaminated corn (10,11). Fumonisin B1 has been shown to cause equine leucoencephalomalacia (12), porcine pulmonary edema (13), and promotion of liver tumors in rats (14). Recent surveys indicate that high levels of fumonisin B1 are present on United States feeds associated with field cases of these animal diseases (15).
The molecular mechanism of action of the fumonisins is not known. However, this invention provides the discovery that these compounds bear a remarkable structural similarity to sphingosine, the long-chain (sphingoid) base backbone of sphingomyelin, cerebrosides, sulfatides, gangliosides and other sphingolipids. Sphingolipids are thought to be involved with the regulation of cell growth, differentiation, and neoplastic transformation through participation in cell-cell communication and cell-substratum interactions; and possible interactions with cell receptors and signalling systems (16-20). This invention provides that fumonisins and fumonisin analogs target the disruption of sphingosine metabolism and that fumonisins and fumonisin analogs inhibit de novo sphingolipid biosynthesis in animals. This invention further identifies the reactions catalyzed by ceramide synthase as important sites for altering sphingolipid metabolism. This core discovery of the biochemical action of fumonisins provides a means to treat the many diseases associated with sphingolipid metabolism as well as a means for early detection of fumonisin contamination or ingestion.
This invention provides a method of altering the metabolism of sphingolipids in a cell, comprising contacting the cell with a fumonisin or an analog thereof. Also provided is a method of treating an abnormal condition in a subject associated with an alteration in sphingolipid metabolism comprising administering a fumonisin, or an analog thereof, to the subject in a metabolism altering amount. In addition, a composition comprising a fumonisin, or an analog thereof, in a pharmaceutically acceptable carrier is provided. As used herein xe2x80x9ca fumonisinxe2x80x9d only includes those fumonisins with the metabolism altering activity.
Also provided is a method of treating an abnormal condition in a subject associated with the ingestion of a fumonisin, or an analog thereof, which results in the depletion of a sphingolipid in the subject, comprising adding an amount of the sphingolipid to the subject sufficient to treat the condition. Further provided is a method of treating an abnormal condition in a subject associated with the ingestion of a fumonisin, or an analog thereof, which results in the accumulation of a sphingolipid, comprising adding an amount of an inhibitor of the sphingolipid to the subject sufficient to treat the condition.
The invention also provides a method of detecting the consumption of a fumonisin, or an analog thereof, in a subject comprising (A) detecting, in a sample from the subject, the state of the metabolic pathway of sphingolipids and (a) comparing the state of the metabolic pathway to that of a normal subject, the presence of a change in the stat of the metabolic pathway indicating the consumption of a fumonisin or a fum nisin analog. Also provided is a method of detecting the presence of a fumonisin or fumonisin analog contamination in a sample from a food or feed comprising detecting a reaction in the metabolic pathway of sphingolipids, the presence of the reaction indicating the presence of a fumonisin or fumonisin analog contamination.
Furthermore, the invention provides a method of diagnosing an abnormal condition in a subject associated with an alteration in sphingolipid metabolism comprising detecting the state of the metabolic pathway of sphingolipids in a subject and comparing the state of the metabolic pathway to that of a normal subject, the presence of a change in the state of the metabolic pathway indicating the presence of an abnormal condition.
Finally, this invention provides for novel fumonisin analogs and compositions comprising fumonisins and fumonisin analogs.